Aim: This study examined the effect of aerobic exercise with and without blood flow restriction on exercise-induced hypoalgesia and endogenous opioid and endocannabinoid systems. Methodology: In a randomised crossover design, pain-free individuals performed 20 min of cycling in four experimental trials: 1) Low intensity aerobic exercise (LI-AE) at 40% V̇O2max; 2) LI-AE with low pressure BFR (BFR40); 3) LI-AE with high pressure BFR (BFR80); and 4) High intensity aerobic exercise (HI-AE) 70% V̇O2max. Pressure pain thresholds (PPT) were assessed before and 5 min post-exercise. Circulating concentrations of beta-endorphin and 2-arachidonoylglycerol were assessed before and 10 min post-exercise. Results: In the exercising legs, post-exercise PPTs were increased following BFR40 and BFR80 compared to LI-AE (23-32% vs 1-2%, respectively). Post-exercise PPTs were comparable to HI-AE (17-20%) with BFR40 and greater with BFR80 (30-32%). Both BFR80 and HI-AE triggered comparable systemic hypoalgesia in remote areas of the body (26-28% vs 19-21%). Post-exercise circulating beta-endorphin concentration was increased following BFR40 (11%) and HI-AE (14%, with the greatest change observed following BFR80 (29%). Post-exercise circulating 2-arachidonoylglycerol concentration was increased following BFR40 (22%) and BFR80 (20%), with the greatest change observed following HI-AE (57%). Conclusion: Addition of BFR to LI-AE can trigger both local and systemic hypoalgesia that is not observed follow LI-AE alone and activate endogenous opioid and endocannabinoid systems of pain inhibition. Compared to HI-AE, local and systemic hypoalgesia following LI-AE with high pressure BFR is greater and comparable, respectively. LI-AE with BFR may help pain management in load compromised individuals.